Research progress on mechanisms and predictive biomarkers for immune-related adverse events

doi:10.21203/rs.3.rs-2494743/v1

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Research progress on mechanisms and predictive biomarkers for immune-related adverse events

https://doi.org/10.21203/rs.3.rs-2494743/v1

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In recent years, immune checkpoint inhibitors (ICIs) have been widely used in patients with malignant tumors. While ICIs significantly improve the prognosis of cancer patients, immune-related adverse events (irAEs) also occur. It is currently believed that the occurrence of irAEs correlates with alterations in the body's autoimmune system function, including over-activation of the immune system and breakdown of autoimmune tolerance. The mechanisms involve direct activation of T cells, secondary B-cell defects or autoantibodies production, ectopic antigen or antigenic epitope spread, and genetic susceptibility. Understanding the mechanisms of these toxic reactions and clearing predictive biomarkers will limit their occurrence, improving the prognosis of cancer patients treated with ICIs and giving early intervention to reduce the risk and damage associated with their occurrence. This review will systematically list possible mechanisms for the occurrence of irAEs and promising predictive biomarkers, and summarize approaches for early intervention and treatment, suggesting possible future directions for follow-up research and clinical applications of irAEs.

Immune-related adverse events

Immune checkpoint inhibitors

Mechanisms

Biomarkers

Intervention

Cancer

Our deep understanding of adaptive immunity at the molecular level has facilitated immunotherapy advances over the past few years. The clinical use of ICIs commenced with ipilimumab [a fully human, IgG1κ monoclonal, anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) IgG1 antibody], followed by pembrolizumab [a humanized, engineered, monoclonal, anti-programmed cell death protein 1 (PD-1) IgG4 antibody] and nivolumab (a fully human, monoclonal, anti-PD-1 IgG4 antibody) [1]. Subsequently, antibodies against programmed cell death 1 ligand 1 (PD-L1) have emerged. However, the clinical application of these drugs has led to specific immunomodulation-related adverse reactions through upregulation of the immune response, called immune-related adverse events. According to the statistics, 94.9% of patients experienced at least one irAEs, and 55.4% experienced at least one grade 3–4 irAEs [2]. IrAEs occur at any time following treatment with ICIs, generally within 1–6 months; however, they can also happen a few days after therapies or more than 1 year at the end of the treatments with ICIs [3].

ICIs enhance the activity of T cells against antigens in tumor cells and normal tissues and increases autoantibodies and cytokine levels. These processes lead to excessive activation of the body's immune system, breakage of autoimmune tolerance, or greater sensitivity to antigen recognition and attack on normal tissues [4, 5]. The toxicity can affect almost all tissues and organs in the body through the initiation and activation of T and B lymphocytes (T and B effector cells). Such signaling indicators reflect changes in the molecular structure and function of cells, and abnormalities in the biochemical metabolism of normal tissues can manifest as changes in biomarkers. The measurement of biomarkers provides information on the current biological processes in normal tissues or organs of cancer patients treated with immunotherapy, thus predicting the occurrence of irAEs.

With the widespread development of immunotherapy clinical trials, the onset of irAEs and their effective management are of increasing concern and hot debate by clinicians. Early identification, diagnosis, and treatment are of great importance. In addition to biomarkers and population characteristics, we should incorporate imaging studies to aid in diagnosis. On the other hand, researchers have explored the molecular mechanisms of irAEs and related predictive markers more deeply by developing precise detection technologies and have made many new advances in the critical theory and understanding of their occurrence and prediction.

Immune checkpoint blockade primarily acts in intrinsic and extrinsic ways: one is to enhance the activation of specific anti-tumor immune responses, and the other is to attenuate the immunosuppressive function exerted by the TME (tumor microenvironment) through various cytokines. At a cellular level, the immune cell subtypes involved in the expression of target molecules may cause the development of immune-related adverse reactions by disrupting normal tissue T cell de-suppression, secreting high levels of cytokines, disrupting intestinal homeostasis, or altering genetic susceptibility at the genetic level (Fig. 1). There are ongoing investigations into how these interconnected immune components contribute to irAE pathogenesis [6], and the following sections highlight the specific mechanisms and findings to date.

Direct activated T-cell attack

ICI therapy uses monoclonal antibodies to inhibit the expression of proteins. CTLA-4 acts in the early stages of T cell activation, while PD-1 and its ligand (PD-1/PD-L1) inhibit activated T cells in the late phases of the immune response, leading to T cell depletion [7]. ICIs act on T lymphocytes in the periphery and those infiltrating into tumor tissues after systemic administration. They disrupt effector T cell tolerance, especially CD8⁺ T cells, while fighting tumors and cause an active proliferative state, regulatory T cell depletion and functional suppression, common antigen cross-presentation, and altered genetic susceptibility, thus non-specifically disrupting immune homeostasis in non-tumor tissues and producing severe off-target immune and inflammatory responses (Fig. 1a).

Disrupt immune tolerance of normal tissue

Immune checkpoints are negative regulators of T-cell function and regulate self-tolerance and immune homeostasis, a process that allows the immune system to protect its own tissue cells [4, 5]. Hence, when ICI is used to block immune checkpoint molecules, it may alter the body's immune state by reactivating autoreactive T cells eliciting an autoimmune response or inducing a significant inflammatory attack in sub-clinically inflamed organs. CTLA-4 is an essential regulatory protein for T cell initiation and activation. It is expressed on naive T cells in the central lymph node during the early stage of the immune cycle [8]. CTLA-4 shuttles from intracellular vesicles to the surface of T cells and then competes with CD28 on T cells to bind B7-1 (CD80) and/or B7-2 (CD86) on antigen-presenting cells, reducing the number of activated antigen-specific T cells [9, 10], thereby mediating immune escape from target tissues and maintaining immune tolerance in normal tissues. It is known that PD-1, once bound, induces phosphorylation of tyrosine residues within immunoreceptor tyrosine-based switch motif (ITSM) located in the cytoplasmic tail, leading to recruitment of phosphatases SHP1 and SHP2 and dephosphorylation in downstream effectors such as Syk, PI3K and CD3 [11]. When ICIs inhibit PD-L1 linkage to PD-1, they activate PI3K-AKT and Ras-Raf-MEK-ERK signaling pathways, causing the proliferation and differentiation of effector T cells [12]. Therefore, immune checkpoint blockade breaks this homeostasis by acting on CB8⁺ T cells and reducing inhibitory signals to T cells delivered via protein phosphatase 2A (PP2A) and lipid rafts or splice variants [13–15]. This imbalance destabilizes effector T cell tolerance and leaves normal tissues in a state of immune hyperactivation, which causes immune-related adverse reactions.

Forkhead box protein 3⁺ (FoxP3⁺) regulatory T cells constitutively express CTLA-4 [16]. Regulatory T cells (Tregs) typically suppress the antitumor immune response. After systemic dosing of ICIs, several studies have shown depletion of Tregs and functional suppression in the organism. Researchers showed that [17, 18] IgG2a-specific antiCTLA-4 antibodies induce antibody-dependent cell-mediated cytotoxicity (ADCC) effects against Foxp3⁺ Treg at tumor sites. The Fb segment of ICIs binds to specific antigens on Foxp3⁺ Treg, and IgG2 subtype preferentially integrates with human fragment crystalline γ receptor (FcγR) expressed by immune effector cells (natural killer cells, macrophages) [18], inducing secretion of cytotoxic substances as granzyme B and perforin, which damages regulatory cell membranes, leading to cell disintegration and Tregs apoptosis. Alternatively, ICIs can mediate the direct killing of Tregs by effector cells through Fas/FasL pathways and TNF-α/TNFR-1 pathways. Similarly, PD-1/PD-L1 axis controls Foxp3 alterations in Tregs and anti-PD-1 causes a Foxp3 reduction, which diminishes functional inhibition of Tregs [19]. Hence, some Tregs apoptosis appears to be exhausted in number or Foxp3 decline arises in dysfunction after application of immune checkpoint blockade in patients with advanced cancer, then Tregs' inhibitory effect on T cell activation and proliferation in normal tissues is weakened, resulting in abnormally activated T cells killing natural tissues and organs, spoiling autoimmune tolerance.

Abnormal activation of autoreactive T cells

Cytokines [20] (IFN-γ, inducible chemokine, NLRP3) secreted by activated CD8⁺ T cells and Th1 cells after immune checkpoint blockade promote further activation of T cells to kill tumor tissue while aberrantly activating other non-targeted sites of autoreactive adaptive, innate immune cells [21, 22], which may be another mechanism for the occurrence of irAEs.

Lymphocytes in the gastrointestinal tract coexist with symbiotic bacteria in a labile immune-responsive environment. Intestinal mucosal microorganisms promote nutrient metabolism and absorption, participate in the programming of intestinal CD4⁺ and CD8⁺ T cells and maintain their practical function. Immune tolerance in the genital tract is mainly mediated by various isoforms of Treg expressing CTLA-4 or PD-1 in intestinal mucosa and mesenteric lymph nodes to guard against aberrant immune responses. The gut microbial diversity and composition of responding and non-responding patients receiving anti-PD-1 therapy are different [23]. For this reason, ICIs targeting Treg enable effective restoration of antitumor immune response along with upsets of intestinal immune homeostasis, reprogramming relevant intestinal flora by autoreactive T cells and immune imbalance in non-targeted tissues in patients with advanced cancer [24, 25]. Some researchers proposed that adenosine 5'-triphosphate derived from intestinal commensal bacteria stimulates differentiation of Th17 cells, and differentiation or expansion of intestinal mucosal Th17 cells is greatly influenced by intestinal flora components [26], then Th17 further secretes IL-17 [22]. This plays a role in the pathogenesis of some irAE mechanisms and the recovery of anti-tumor immunity. As a result, immune checkpoint blockade disrupts homeostasis between lymphocytes and preexisting or newly recognized pathogenic or commensal microbes in the weak immunoreactive environment, causing dysregulation of intestinal immune homeostasis and affecting immune response and treatment-related toxicity. However, the specific role of various microbes in the aberrant activation of autoreactive immune cells has not been clarified and further prospective studies are needed.

Common antigen cross-presentation

T cell receptors (TCR) are characteristic markers on the surface of all T-cells. 90–95% of TCRs consist of two peptide chains in peripheral blood, α and β, each of which can subdivide into variable (V), constant (C), transmembrane, and cytoplasmic regions. TCR molecules belong to the immunoglobulin superfamily, and their organic antigenic specificity is present in V region (Vα, Vβ), which determines antigen binding specificity of TCRs and Vβ receptor library screening can identify clonal proliferation. TCR recognizes CD8⁺ T cells and releases granzyme B and perforin to kill tumor cells. In this process, someone found a significant increase in the number of peripheral T cells with TCR Vβ in patients who developed organ-specific immune responses after anti-CTLA-4 antibody treatment [27], suggesting that immune checkpoint blockade exerts anti-tumor effects in parallel with stimulating TCR Vβ-bound autoreactive T cells in specific organ tissues and activating infiltrating T cells against normal tissue cells by activating the pernicious effect of them and eliciting autoimmune responses.

In addition, T cell clones in the lesioned tissues of irAEs significantly overlap with tumor-infiltrating T cells by TCR sequencing [20, 28–30], which indicates that T cell populations recognize common antigens shared in tumor and normal tissues and produce circulating antibodies, leading to abnormal immune responses in organs, another mechanism by which immune-related toxicity occurs.

B Cells and autoantibodies

After anti-PD-1/PD-L1 therapy, the PD-1hi regulatory B-cell subset can activate the tumor-specific T-cell response via IL-10-dependent pathways [31] or foster BCR signaling by inhibiting PD-1 recruiting SHP-2 to its phosphorylation and dephosphorylating key signal transducers of BCR signaling [32]. This is the process of B-cell deficiency secondary to congenital T-cell hyperactivation (CTLA-4 deficiency).

Activated B-cell subsets (CD21loB cells and antibody-producing plasma cells) accumulate in periphery. They activate humoral immunity to attack autoantigens [31–33], allowing immune reactions between sensitive antigens and their own occult or elicited autoantibodies, damaging non-targeted tissues and organs. Although data on B-cell changes after ICB treatment are limited, evidence of B-cell autoreactivity is clear under certain circumstances. Immunotherapy-activated antibodies bind to many receptors in the body, inducing a series of autoimmune responses with receptors, antibodies, and complement. Nevertheless, the role of B-cells in hepatitis and related toxicities is controversial. Since the number of CD20⁺ B cells in circulating tissues of patients presenting with adverse reactions is significantly lower than in patients with drug-induced liver injury [34], this result contradicts previous findings. This may vary due to the unclear relationship between the circulating B-cell subpopulation and specific irAEs, which still needs further investigations in more clinical models (Fig. 1b).

Ectopic antigen expression and antigenic epitope diffusion

CTLA-4 has a low expression in native T cells but is highly induced by TCR in recognition of pathogens or tumor antigens on CD4⁺ T cells and CD8⁺T cells [35], and CTLA-4 and its ligands appear more abundantly exposed on secondary lymphoid organs [36]. (Fig. 1c) This provides conditions for ICIs (immunoglobulin G1 subclass) to attach to ectopic antigen, CTLA-4, expressed on normal tissues directly such as anterior pituitary cells [37], which further mobilizes complement cascade to deposit C3d, C4d complement components [38], and a complement-mediated inflammatory cascade similar to the type II hypersensitivity reaction occurs, referring to immune-related adverse reactions.

Antigen epitope spreading denotes secondary (non-targeted) tumor antigens released by tumor cell death during the immune response. It triggers immune responses in other tissues and organs by spreading [39], which also explains the lag and delay of immune responses to some extent. Tumor cells disintegrate and destroy, releasing non-targeted tumor antigens and spreading to normal tissues and organs; immune effector cells recognize these antigens to trigger an immune response.

Genetic predisposition affects individual susceptibility

Germline genetic variants (genetic susceptibility), which cover unique human leukocyte antigen (HLA) haplotypes or single nucleotide polymorphisms (SNPs) in different genetic, epigenetic, or immunomodulatory genes are associated with a variety of classic autoimmune diseases [40] and play an essential role in the development of irAEs (Fig. 1d). HLA markers, DQ8 and DR53, implicate lymphocytic pituitary inflammation [41]; HLA-DR4 dominates as an influencing factor in patients presenting with autoimmune insulin-dependent diabetes mellitus after PD-1/PD-L1 treatment [42]. Researchers [43] identified and selected 166 SNPs of 86 genes using sequenom MassArray iPLEX assay (Agena Bioscience) and understood toxicity as a treatment effect outside the pre-supposed specific tumor target. They found that rs4845618 (IL6R), rs10964859 (IFNW1), and rs3087243 (CTLA4) have the potential to influence gene expression and these unique immune genetically related gene SNPs can predict the efficacy and safety of anti-PD1/PD-L1 therapies. [44] In parallel, one team constructed a WT mouse model and another lacking miR-146a. These models revealed that SNP rs2910164, which led to reduced miR-146a expression, was associated with an increased risk of severe irAEs at baseline and during ICI treatment, reduced progression-free survival, and increased neutrophil counts. This may serve as a biomarker to predict severe irAEs in ICI-treated patients. Although these genome-wide association studies (GWAS) in small samples have identified germline genetic variation following partial immunotherapy as a potential mechanism, we do need studies in large patient cohorts to identify solid genetic associations for developing irAEs.

Several biological indicators correlate with irAEs during the occurrence of abnormal immune responses. Although none of the biomarkers have been definitively validated to predict irAEs, some may have clinical applications. Several biomarkers emerge after the onset of irAEs; they get evaluated after treatment. In addition to their prospective clinical utility, these biomarkers confirm the mechanism by which irAEs occur. Below we will review several classes of biomarkers and discuss their relations with the aforementioned ICIs-related toxicity (Fig. 2).

T cell-related biomarkers in TME

T cells represent essential targets for ICIs. Some evidence suggests that they play roles in irAEs through decreased clonality, increased TCR diversity, and defective Treg function. Moreover, immune infiltrating cells in TME can also affect T cells' function by secreting related proteins (Fig. 2a).

One mouse model of paraneoplastic neurological disease found that antigen-specific T cells migrated into the cerebellum and CD8⁺ T cells caused significant neuroinflammation and paraneoplastic neurological disease by killing Purkinje neurons after anti-CTLA4 treatment [45]. In this study, T-cell clones were detected by their presence in peripheral blood and possibly by next-generation sequencing (NGS) to provide early indications of irAEs. Investigators carried out single-cell RNA sequencing on biopsy tissue samples from colitis; they reported a significant accumulation of CD8⁺ T cells that share TCR sequences with tissue-resident memory cells [46]. This suggests that changes in TCR diversity are associated with GI toxicity. The pathogenesis of ICIs-induced nodular disease is unclear, but it is noteworthy that CTLA4 expression decreases in Tregs in patients with nodular disease after the application of immune checkpoint blockade, causing defective Treg suppression. In comparison, no specific serum manifestations have been found for ICIs-induced nodular disease [47, 48].

The bivariate regression model of T cell-activated lymphocyte cytosolic protein 1 (LCP1) and ADP-dependent glucokinase (ADPGK) combined pharmacovigilance data and omics data to assess the association between multi-omics factors and odds of reporting irAEs in different cancer types, suggesting that combination of them has the best predictive for irAEs accuracy [49]. However, the forecasting value of LCP1 in diverse tumors is unclear and still needs further validation. CD163 is a receptor expressed by anti-inflammatory (M2) macrophages. It mainly locates in TME. M2 macrophages are characterized by their immunosuppressive properties, thus correlating with poor prognosis. In autoimmune diseases, as well as melanoma patients during anti-PD1 therapy [50], soluble CD163 (sCD163) obtained by proteolytic shedding of the receptor arose. A study showed that the density of CD163⁺ M2 macrophages was associated with inadequate recovery of immune-related renal function. In addition, researchers found an abnormity in the absolute rate of change concerning CD163 in serum: a significant increase in patients with irAEs compared with those without symptoms [51]. The soluble CTLA-4 isoform (sCTLA-4) engages in membrane-bound isoform inhibition [52] and blocks the interaction between full-length CTLA-4 and Tregs and B7 ligands expressed by self-reactive T cells, thereby enhancing T cell cytotoxicity and reducing Treg cells' immunosuppressive function, known as increased T cell activation. Analysis of sera from IPI-treated MM patients by ELISA revealed that higher baseline sCTLA-4 levels were associated with any irAEs (P = 0.029), particularly in the digestive tract [53].

Hence, the abnormal subset of T cell clones found in inflammatory tissues and blood circulation suggests that detecting activated T cells in peripheral blood may be an early indicator of the occurrence of irAEs. Second, the relationship between detecting immune-infiltrating lymphocyte-associated proteins activated in TME and different types of immunotoxicity still needs further investigation. Ultimately, the concentration of soluble biomarkers in the peripheral circulation of the organism exerts essential roles in predicting the occurrence of irAEs and verifying their involvement in the mechanism of T-cell-induced irAEs.

B cell biomarkers

Despite predictive biomarkers of ICB and strategies to enhance clinical response focused on the T-cell compartment, early B-cell changes are proposed to predict irAEs after anti-PD-1 and anti-CTLA-4 combination therapy [54]. The presence of tissue-specific autoantibodies after treatment and high baseline autoantibody levels detected prior to treatment are associated with the subsequent occurrence of irAEs, which supports the idea that some mechanisms of immunotherapy-related toxicity are mediated by B cells (Fig. 2b).

Researchers analyzed immune cells from a small peripheral blood sample. High proportions of CD19⁺ B cells link to grade ≥ 3 (OR = 0.063, P = 0.02) and grade ≥ 2 (P = 0.051) irAEs, although the latter showed only a significant trend. In addition, a prospective study showed that patients with a more than 2-fold increase in CD21lo B cells and plasma cells tended to develop irAEs [54]. This minor finding may indicate CD21lo B cells as a promising source of toxicity-associated autoantibodies.

Previous studies have identified many auto-specific antibodies in various organ tissues. ICIs imbalance the body's immune system, producing specific antibodies that recognize and bind platelets, such as αIIbβ3 and GP1b antibodies, which continuously remove platelets from peripheral blood by activating the monocyte-macrophage system in the body [55, 56]. For example, nivolumab induced and increased the production of platelet-specific IgG antibodies, which could destroy platelets and lead to immune-related thrombocytopenia, in patients with non-small cell lung cancer (NSCLC). One mouse model purified a cardiac-specific 30 kDa protein from heart extracts and identified it as cardiac troponin I (cTnI). Mice lacking the PD-1 immunosuppressive coreceptor developed autoimmune dilated cardiomyopathy and produced high titers of autoantibodies against a cardiac-specific 30 kDa protein.

Defined baseline high levels or abnormal increases in autoantibodies correspond to tissue-specific irAEs. Several studies have already detected specific autoantibodies in patients with endocrine irAEs. Among them, patients with pituitary dysfunction show increased titers of anti-guanine nucleotide-binding protein G (olf) subunit alpha and anti-integrin 2B antibodies [57], and anti-pituitary antibodies (APAs) can predict the presence of pituitary autoimmunity measured by indirect immunofluorescence [38]. It is unclear whether APAs are positive at baseline or before the onset of pituitary dysfunction. Therefore, we need further studies to clarify the utility of APAs as biomarkers of pituitary irAEs. Interestingly, anti-GAD, anti-IA2, and anti-zinc transporter 8 antibodies were positive prior to initiation of ICI therapy in a patient with ICI-induced Type 1 diabetes mellitus (T1DM) [42], suggesting these autoantibodies being biomarkers that suggest the presence of T1DM in a subset of patients at baseline. Implicated antigenic targets for bullous pemphigoid (BP) include the hemidesmosomal structural proteins of the dermoepidermal junction, BP180 (collagen XVII), and BP230 [58]. Serological detection revealed elevated antibodies against BP180 and BP230. Another study [59] measured serum levels of BP180, BP230, and type VII collagen in patients receiving PD-1/PD-L1 inhibitor treatment at baseline and 8 weeks post-treatment. The results showed that increased autoantibody production against hemidesmosomal protein BP180 IgG was significantly correlated with skin irAEs only at baseline, but not with BP230 and type VII collagen.

In general, B cell-related biomarkers are mainly precursor B cells and autoantibodies. While using autoantibodies to predict irAEs offers the edge of application: pre- and post-treatment sera of ICIs are readily available, and the relationship between their baseline levels and immunotoxicity in various organ tissues can be easily verified.

Antigen-related biomarkers

The same antigenic epitopes in tumor tissues and other organs can enhance their recognition through cross-presentation, so common antigen overexpression indicates the occurrence of irAEs. Besides, the original antigens may be recognized as non-self substances and cross-react after systemic application of ICIs. Their specific antigenic determinant clusters require further exploration as risk factors (Fig. 2c).

One study performed NGS using myocardial T cells and tumor T cells from patients who developed fatal myocarditis, they identified high levels of muscle-specific antigens (desmin and troponin) in the tumors [60], suggesting that T cells probably target antigens shared by melanoma, skeletal muscle, and heart. It is hypothesized that immune-mediated myocarditis results from the over-activation of adaptive immune responses that target common epitopes of myocardial and tumor cells. Typically, PD-L1 and PD-L2 are expressed on sundry types of self-cells (tubular epithelial cells, endothelial cells, fibrillary reticulocytes, pancreatic islet cells, astrocytes, and neurons), reducing autoimmune reactions and host organ injury [11]. In vitro, pretreating IFNg-stimulated HK-2 cells with anti-PD-L1 significantly enhanced co-cultured and mitogen-activated Jurkat or IL-2 secreted from human peripheral blood T cells [61]. PD-L1 overexpression serves as a central mechanism for inducing immunosuppression; T cells undergo apoptosis and overexpression, impairing vascular permeability in other tissues and organs. Therefore, we hypothesized that PD-L1 overexpression may be a potential biomarker to predict the occurrence of irAEs.

Some patients underwent a mild cross-reactivity between tumor antigens and dorsal root ganglia (DRG) after immunotherapy. Pembrolizumab upregulates cytotoxic T-cell responses to DRG via activating the slaughter of cancer cell cycle and subacutes sensory impairment [62]. It is reasonable to hypothesize that an intrinsic kidney antigen, initially tolerated but recognized as non-self with the brake of CTLA-4/PD-1 signaling in self-reactive T cells, could be responsible for acute tubulointerstitial nephritis [63, 64].

Cytokine-related biomarkers

Cytokines are small secreted proteins. (Fig. 2d) As means of intercellular communication, they act locally and distantly to influence cellular responses and cause intercellular coordination. ICIs may tilt the balance of this environment toward inflammation and autoimmunity [65].

Chemokines, a group of low molecular weight peptides, induce chemotaxis of different leukocyte subtypes and function primarily to recruit leukocytes to sites of inflammation and play a role in tumor growth, angiogenesis and organ sclerosis. Endocrine epithelial cells secrete CXCL9, CXCL10, and CXCL11 after IFN-γ stimulation, which in turn migrate CXCR3-expressing type 1 T helper lymphocytes and emit IFN-γ. Thereby they mediate autoimmune inflammation sustaining in endocrine glands [66]. The proportion of circulating CXCR4⁺ T cells and CCR7⁺ B and T cells (but not CXCR5) in peripheral blood mononuclear cells (PBMC: lymphocytes + monocytes) is significantly reduced in patients with autoimmune thyroid disease. This systemic effect of active intrathyroidal lymphoid tissue is a possible novel marker of thyroid autoimmune disease activity. The B-cell sequestrant CXCL13 mainly exists in mature B cells, CD4⁺ follicular Th cells, and activated Treg cells and takes part in autoimmune, inflammatory diseases [67].

Aside from organ specificity, cytokine levels may be associated with the onset and severity of irAEs. Inflammation has an integral role in the mechanisms. The specific milieu of circulating cytokines promotes and reflects changes in systemic immune responses, including anti-inflammatory cytokines (IL-10, TGF-β), pro-inflammatory innate immune cytokines (IL1, IL-6), and pro-inflammatory adaptive immune cytokines (IFN-γ, IL-17) [68]. The central pro-inflammatory cytokine IL-6 in plasma is commonly elevated in inflammatory arthritis after ICI treatment. Baseline serum IL-6 levels regressed negatively with the incidence of irAEs in melanoma patients treated with ipilimumab [69]. Surprisingly, an increase in IL-6 levels after ICI treatment was relevant to irAEs. In patients presenting with immune-associated refractory esophageal strictures, a pathogenic pro-inflammatory CD4⁺ T cell subpopulation expressing IL-17a (c-Kit-CD161⁺ MDR1⁺ Th17 cells) serves a vital role in the refractory autoimmune response [70], and IL-6 induces the maturation of naïve CD4⁺ T cells into Th17 cells. As a result, the IL-6-Th17 pathway may function in the pathogenesis of irAEs. Effective treatment of colitis with tocilizumab or infliximab [69] has also been shown to correlate with high levels of cytokines IL-6 or TNF, respectively. Moreover, elevated baseline serum IL-17 levels were similarly associated with an increased risk of diarrhea and severe colitis. Thus, these studies suggest IL-6 and IL-17 as predictive markers for developing irAEs. One study divided 26 patients with advanced malignant diseases treated with ICIs into two groups: those who presented with thyroid irAE and those who did not. Higher levels of serum IL-1β, IL-2, and GM-CSF at baseline were found when measured before and at 4 weeks of treatment, while early decreases in IL-8, G-CSF, and MCP-1 were significantly associated with thyroid irAEs [71].

Cytokines have diversity, posing challenges for assessing the clinical relevance of irAEs. Consequently, we warrant prospective studies involving larger cohorts to determine the clinical utility of cytokine analysis tools.

Blood cell biomarkers

Blood cell count is a routine clinical test. It has received extensive attention as a highly available specimen and a signal for irAEs, and the primary focus has been on leukocytes, neutrophils, lymphocytes, and eosinophils (Fig. 2e).

Multivariate logistic regression analyses showed that pre-treatment neutrophil-to-lymphocyte ratio (NLR) < 4.3 was significantly correlated with the risk of grade 3–4 irAEs, while the rate of change in NLR after treatment, ΔNLR > 120% were remarkably associated with increased risk [72], suggesting NLR a valid prognostic and morbidity in grade 3–4 irAEs marker. This may be because of the balance among circulating neutrophils and lymphocytes, which reflects anti-tumor forces. In turn, dysregulation of this balance might ascribe to the pathogenesis of irAEs. In a clinical trial, patients treated with ipilimumab showed increased levels of neutrophil activation markers CD177 and CEACAM1 and a higher risk of gastrointestinal irAEs [73]. The possible mechanism is that activated neutrophils spread inflammation to organs, subsequently causing tissue damage; On the other hand, they control the activation of T and B cells through antigen expression and cytokines. However, a colonoscopy in patients using ipilimumab for 1–2 weeks revealed focal neutrophilic cryptitis, neutrophilic infiltration, excess plasma cells in lamina propria, and lymphocytic cryptitis increased 3 weeks before the appearance of symptoms of colitis (grade 2 or higher diarrhea) [74]. Researchers also concluded that these findings lack reliability as biomarkers for predicting immune-mediated colitis in the clinical setting [74]. As such, activated neutrophils are controversial biomarkers for predicting ICB-associated intestinal irAEs.

Recently, researchers provided evidence that ICIs act on lung tissue after activation of Th2 cells, and serology shows eosinophil formation [75]. A high peripheral eosinophil count is relevant to the incidence of gastrointestinal irAEs and a generalized maculopapular rash [76, 77]. One mouse model used a combination of CTLA-4 blocking antibody 9D9 and/or indoleamine 2,3-deoxygenase 1 (IDO1) inhibitor epacadostat (mimic the effects of PD1 blockade) in wild-type and PD-1(-/-) mice [78]. This synergistically induced immune-associated liver injury and immune cell infiltration and found sites of hepatocyte necrosis frequently surrounded by mononuclear immune cells. ICIs increased the expression of genes pertaining to hepatocyte death, leukocyte migration, and T cell activation in the liver, and synergistic action of anti-PD-1 and CTLA-4 with IDO1 triggered this process.

Peripheral blood markers, including lymphocyte and eosinophil counts and neutrophil-to-lymphocyte ratios [79], have led to more practical clinical applications because of their invasiveness and ease of routine measurement, but are not widely used to predict the occurrence of irAEs due to their poor specificity. Notably, the accuracy and reliability of blood counts as predictors of irAEs still need further weighing and validation.

Genomic biomarkers

HLA is a highly polymorphic complex consisting of closely linked gene seats (Fig. 2f). It contains abundant alleles, and the variants are unique and may correlate with the occurrence of certain irAEs. [80] There is a significant association between the human leukocyte antigen HLA-DQB1*03:01 and colitis in malignant melanoma patients treated with nivolumab. Researchers compared the HLA allele frequencies of 11 cancer patients who developed endocrine dysfunction after ICB treatment with the Japanese HLA haplotype database and found that HLA-DR15, B52, and Cw12 may be susceptibility factors for pituitary irAEs (induced secondary adrenal insufficiency) [81]. One small sample study suggested a predominance of HLA-DR4 in patients with ICI-induced autoimmune T1DM [42]. A higher frequency of HLA-DQB1*06:01, DPB1*09:01, and DRB5*01:02 was reported in another study [82]. Therefore, the HLA haplotype can be used as a predictive marker for pituitary irAE. A clinical trial enrolled patients with advanced cancer treated with ICIs. Those with a genetic variant of human leukocyte antigen, HLA-DRB1*11:01, tended to develop pruritus [80]. Two advanced cancer patients carrying HLA class II (HLA-II) germline alleles HLA-DRB1*15:01 and HLA-DQB1*06:02 susceptible to systemic lupus erythematosus (SLE) may trigger immune-related SLE [83].

In short, genetic markers suggest early irAEs, and the association between their specific SNPs and specific tissues remains to be investigated.

Autoimmune disease

In order to avoid disease flares in patients with advanced cancer who have autoimmune diseases of their own, we generally exclude the use of immunotherapy in such individuals when conducting studies of clinical ICIs. However, the association between a history of autoimmune disease and irAEs has been confirmed in some experimental models or patients without treatment according to the protocol. A study [84] established a mouse experimental autoimmune myocarditis model by intraperitoneal injection of α-myocardial heavy chain (MyHC-α) fragments into mice. They administered anti-PD-1 antibodies (mPD1ab) to mice at two-time points, simultaneously with and after MyHC-a fragment administration, and observed that ICI-induced autoimmune myocarditis may be related to the activity of the autoimmune system prior to ICI administration. Subsequent administration of mPD1ab significantly increased infiltration of a cluster of differentiation (CD)4 and F4/80-positive cells compared with those administered concomitantly. This suggests that we should try to avoid the use of ICIs in patients with autoimmune diseases. Patients with preexisting AIDs are at an increased risk of irAEs in advanced cancer patients receiving anti-PD-1 immunotherapy compared to those without. Thus, experience with autoimmune disease is a high-risk factor for predicting irAEs.

Several measures can intervene in the development of irAEs early. Prophylactic use of drugs for prevention in high-risk populations or changes in dosage and duration of ICIs, such as prophylaxis against fungi and other microorganisms, use of proton pump inhibitors or histamine H2 blockers to prevent gastritis, and vitamin D and calcium supplementation to prevent bone loss [85]. Further, investigators can treat the primary tumor by finding new immune checkpoints or other drugs. Next-generation immune checkpoints under investigation include lymphocyte activation gene-3 (LAG-3), T-cell immunoglobulin and mucin-containing domain-3 (TIM-3), B- and T-cell lymphocyte attenuator (BTLA), T-cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T-cell activation (VISTA), and B7 homolog 3 protein (B7- H3) [86]. Given the high structural similarity between LAG-3 and CD4 that should favor its primary binding to MHC-II, other molecules interact with LAG3, such as galectin-3, LSECtin, and a-synuclein. Moreover, the combination of anti-LAG3 and PD-1 was evaluated in patients with unresectable or metastatic NSCLC and metastatic squamous cell carcinoma of the head and neck (NCT03625323).

Several guidelines for managing irAEs have been reported, including interruption of therapy, symptomatic treatment with immunosuppressive agents such as corticosteroids, and others [87]. The Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 categorizes more than 700 symptoms across systems into grades 1 to 5 according to severity. We should closely monitor grade 1 (mild) patients for clinical symptoms; temporarily interrupt immunotherapy for grade 2 (moderate) until symptoms resolve and/or the above laboratory indicators drop below grade 1 criteria when treatment is resumed. If symptoms persist for more than 1 week, corticosteroids [prednisone 0.5-1 mg/(kg•d) or equivalent] should be initiated; for grade 3 (severe) and grade 4 (life-threatening) irAEs, high-dose glucocorticoids [prednisone 1–2 mg/(kg•d)] should be administered as shock therapy when symptoms subside to grade 1 or below and reduce the drugs step by step. Refractory cases with no response in 48–72h may require immunosuppressive therapy with agents such as infliximab. Prior to starting TNF inhibitors, infliximab, hepatitis B and C and latent/active tuberculosis are to be pre-tested due to the risk of reactivation [85]. The patients will die upon reaching grade 5 toxicity. It is important to note that ICIs should be permanently discontinued except for endocrine disease controlled by hormone replacement therapy when patients develop grade 4 irAEs [85, 88]. Restart the treatment after recovery. Approaches to re-challenge ICIs have been reported to include class switching: from anti-PD-1 to anti-CTLA-4 and vice versa. The two have slightly different mechanisms of action that make this switch possible. There is evidence in patients with metastatic melanoma that the benefit of class switching when converting from anti-CTLA-4 to anti-PD-1 is mild adverse effects and no discontinuation of therapy [89].

The management of irAEs relies heavily on the application of corticosteroids. Although most irAEs can be controlled and reversed by suspension of dosing and/or corticosteroids, the management process shall focus on the type, dosage, and timing of hormones and enhance medical monitoring, multidisciplinary cooperation and follow guidelines for rational resolution. Emerging data suggest that the systemic immunosuppressive effects of high-dose corticosteroids can negatively affect the efficacy of antitumor therapy. It is crucial to develop new therapeutic agents to alleviate symptoms without compromising efficacy by investigating the mechanisms of irAEs. Various novel therapeutic agents for irAEs have been developed, Currently, several novel therapeutic agents for irAEs have been developed, such as biologics that directly inhibit cytokines and integrins: vedolizumab, a novel drug targeting the α4β7 integrin protein expressed on the surface of bound monocytes; infliximab, an inhibitor of TNF-α; basiliximab, a targeted antagonist of the α chain of IL-2 receptors (CD25 antigen); and tocilizumab, which targets the IL-6 receptor; calcium-regulated phosphatase inhibitors that inhibit the T-cell activator IL-2; cytotoxic agents targeting autoimmune diseases, such as mycophenolate esters, methotrexate, and cyclophosphamide have also shown effectiveness in the management of irAEs. Moreover, individualized treatment of hormone-refractory and rapidly progressive irAEs is challenging. Investigators have proposed a strategy called "shut-off " based on the primary type of immune infiltration aimed at inhibiting key inflammatory components involved in the pathophysiological process of irAEs. It limits the potential adverse effects of pharmacological immunosuppression on tumor response and challenges the stepwise increase approach to pharmacological immunosuppression [88, 90]. Indeed, the availability of other novel biologic agents for refractory irAEs is continuously explored. Investigators have demonstrated many new early interventions and treatments for irAEs. Even though data from validated clinical trial studies still lack, the combination of new evidence and information on irAEs that has gradually accumulated in basic and clinical studies is beneficial in avoiding the risk of irAEs and providing appropriate medications.

Defining mechanisms by which irAEs occur is key to identifying potential predictive biomarkers. Currently known triggers of irAEs include: 1. depletion of Tregs and suppression of their function, increased cytokine release or dysregulation of intestinal immune homeostasis, exacerbation of normal tissue autoimmune responses, common antigen cross-presentation leading to aberrant activation of autoreactive T cells, causing diminished autoimmune tolerance; 2. secondary B cell defects or autoantibody production, damaging non-target sites; 3. expression of ectopic Antigen and antigenic epitope spreading; 4. Genetic susceptibility. These mechanisms detail the process of immune over-activation or immune tolerance in normal tissues. While some possible or relatively straightforward mechanisms for the occurrence of irAEs have been identified, most still need to be clarified and are challenging to explain. Inexplicable or otherwise rare adverse reactions still occur in immunotherapy clinical practice. Consequently, an in-depth investigation of the molecular mechanisms is essential to help clinicians clarify the occurrence of each immune-related toxicity to identify irAEs, administer timely and appropriate treatment rapidly, and scientifically guide the management of adverse reactions from a molecular mechanism perspective.

However, early clinical signs of irAEs are not evident in the practical application of immunotherapy. Once detected, most of them are already grade 3 and above or life-threatening irAEs. Due to the lack of uniform diagnostic criteria for irAEs, many things remain unknown. Therefore, developing simple, measurable, and accurate biomarkers is crucial in predicting the occurrence of irAEs in patients with advanced cancer using ICIs. Currently, many studies have explored various biomarkers, including clonal antigen-specific T cells in tissues and precursor B cells, activated immune infiltrating lymphocyte-associated proteins, soluble membrane receptors and other indicators of the immune cell bank; autoantibodies and identical/similar antigenic determinants; cytokines and inflammatory factors; general clinical testing characteristics such as EOS, MON, LYM, WBC, Neu, NLR; and germline genetic factors. In contrast, several factors identified as predictors of efficacy have been shown to be irrelevant for adverse effects in other studies. Therefore, the challenge of predicting efficacy and irAEs and their interactions may be more complex. There are no clear and valid predictive methods or biomarkers to guide clinical practice. Researchers need to incorporate promising biomarker tests into adequately powered and well-designed clinical trials. For this reason, using these biomarkers for routine testing is not recommended. Secondly, developing novel platforms and high-tech precision assays has enabled researchers to understand the complex network of interactions between various immune cells, cytokines, tumor cells, and normal tissue, improving the sensitivity and specificity of biomarkers for clinical application and analysis. This will facilitate predictive modeling and early detection of irAEs. In addition, we should consider the effectiveness and practicality of biomarkers, including convenience and economy, to fully evaluate the benefit/risk ratio; and to reduce the incidence and severity of irAEs by timely detection and early intervention of treatment during the therapy. This is conducive to clinical decisions and continued optimization of patients' prognosis care protocols for maximum clinical benefit.

Another critical issue is the uniformity of early intervention and treatment strategies for irAEs. Given the diversity of current clinical immunotherapy regimens and the complexity of the corresponding adverse reactions, investigators have explored many aspects of the management of irAEs, including the impact of hormone use on immunotherapy outcomes, challenges of immune retreatment for overall survival benefit in specific patients, exploration of novel agents for irAEs, and individualized management of severe or hormone-refractory adverse reactions. Selective prophylaxis or treatment of high-risk patients relies on corticosteroids, but high-dose or long-term glucocorticoid use may cause adverse effects, such as osteoporosis, elevated blood glucose, hypokalemia, and coagulation dysfunction, which in turn reduce the quality of patients' survival. Adequate studies on pathogenesis provide more targeted interventions to reduce systemic adverse effects caused by hormone shock therapy. In contrast, combination therapy or exploitation of other ICIs may delay effective control of primary diseases and irAEs. Therefore, we do need extensive predictive models, assays, and validation cohorts to clarify the mechanisms of irAEs as well as predictive biomarkers, which may offer guidance for precision and individualization of immunotherapy for patients with advanced cancers.

ICIs Immune checkpoint inhibitors

irAEs Immune-related adverse events

sCTLA-4 Soluble Cytotoxic T lymphocyte-associated antigen-4

PD-1 Programmed cell death protein 1

PD-L1 Programmed cell death 1 ligand 1

TME Tumor microenvironment

FoxP3⁺ Forkhead box protein 3⁺

Tregs Regulatory T cells

IL Interleukin

FcγR Fragment crystalline γ receptor

TCR T cell receptors

HLA Human leukocyte antigen

SNPs Single nucleotide polymorphisms

NGS Next-generation sequencing

LCP1 Lymphocyte cytosolic protein 1

ADPGK ADP-dependent glucokinase

sCD163 Soluble CD163

NSCLC Non-small cell lung cancer

cTnI Cardiac troponin I

APAs Anti-pituitary antibodies

DRG Dorsal root ganglia

NLR Neutrophil-to-lymphocyte ratio

IDO1 Indoleamine 2,3-deoxygenase 1

T1DM Type 1 diabetes mellitus

BP Bullous pemphigoid

SLE Systemic lupus erythematosus

MyHC-α α-myocardial heavy chain

LAG-3 Lymphocyte activation gene-3

Author Contributions All authors contributed to the study conception and design. Yan Zhang and Ziting Qu contributed equally to this work and should be considered as joint first authors. Material preparation, data collection and analysis were performed by Ziting Qu, Tengteng Zhang and Zhiyan Zhao. The first draft of the manuscript was written by Yan Zhang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding This work was supported by Foundation of Beijing Life Oasis Public Service Center (No. cphcf-2022-021) and Key Research and Development Project of Anhui Province (No. 202004j07020044).

Compliance with Ethical Standards:

Data availability statement The data that support the findings of this study are available in MEDLINE repository, [https://www.nlm.nih.gov/medline/index.html].

Disclosure of potential conflicts of interest All authors have no conflicts of interest that are relevant to the content of this review.

Research involving human participants and/or animals This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent As the corresponding author, I verify that all authors significantly contributed to various aspect of the study, have read the manuscript and consented to submit for publication in Molecular Biology Reports.

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Research progress on mechanisms and predictive biomarkers for immune-related adverse events

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Abstract

Figures

Introduction

Mechanisms Of Iraes

Direct activated T-cell attack

Disrupt immune tolerance of normal tissue

Abnormal activation of autoreactive T cells

Common antigen cross-presentation

B Cells and autoantibodies

Ectopic antigen expression and antigenic epitope diffusion

Genetic predisposition affects individual susceptibility

Predictive Biomarkers Associated With Iraes

T cell-related biomarkers in TME

B cell biomarkers

Antigen-related biomarkers

Cytokine-related biomarkers

Blood cell biomarkers

Genomic biomarkers

Autoimmune disease

Early Intervention And Treatment Of Iraes

Conclusions And Prospects

Abbreviations

Declarations

References

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